tbuckley/cabot-search huggingface dataset:
DIPG-50. Bioinformatic evaluation of genes involved in sphingomyelin biosynthesis in Diffuse Midline Glioma H3K27 altered/DIPG: dysregulation of sphingosine 1-phosphate (SP1)
Authors: Aimee Humphreys, Hanna Russell, Helen L Fillmore
Journal: Neuro-Oncology (2022)

Abstract Sphingosine 1-phosphate (S1P), a bioactive signalling lipid, interacts with a network of metabolic enzymes, receptors, transporters, and epigenetic partners. This network is well described in many cancers; however, little is known about its potential impact in DIPG. Expression of HDAC1 (binding target of S1P) and genes associated with the sphingomyelin (SM) pathway were examined in datasets identified in the National Centre for Biotechnology Information, Gene Expression Omnibus, and analysed using the R2: Genomics Analysis and Visualization Platform (http://r2.amc.nl). The Paugh-DIPG dataset (27 DIPG samples) and normal samples (20 years and younger - Berchtold dataset) were compared. To avoid issues related to batch effects, expression values for each gene of interest and controls were exported into separate files to determine differentially expressed genes. Internal genes include housekeeping; ACTB, GAPDH, B2M, TBP; downregulated in DIPG; GPR6, NGB, and upregulated in DIPG; MMP16, PDGFRA, TP53, CSPG4. Genes of interest; SPHK1, SPHK2, SGPL1, ACER1, ACER3, KDSR, SMPD1-4, CPTP, GLTP, DEGS1, CERK, CERS1-6, ASAH1, SGPP1, SGPP2 and HDAC1. To test for significance, each dataset was standardised using ACTB housekeeping gene. Values including Log-transformed fold change were analysed using the non-parametric, Mann-Whitney test. 7 of the 16 genes were dysregulated relative to expression in normal brain (p&amp;lt;0.0002). SPHK2 and SMPD3 were downregulated, and HDAC1, SGPL1, DEGS1, CERS4, and ASAH1 were upregulated in DIPG compared to normal. To identify genes more likely associated with DIPG (vs development), we evaluated gene expression in Brainspan dataset (brspv10rs). Validation of SPHK2 and SGPL1 protein expression (responsible for the synthesis and cleavage of SP1) is underway. Current work is focused on the intracellular processing and function (isoform specific inhibitors) of S1P in DIPG cells. Given its reported role in several cancer hallmarks, a better understanding of the sphingomyelin biosynthesis pathway in DMG/DIPG is merited and may lead to novel therapeutic targets.
Anti-EGFR antibody plus anti-PD-1 antibody and chemotherapy as a neoadjuvant regimen for patients with locally-advanced penile squamous cell carcinoma: A prospective, single-arm, single-center, phase II clinical trial.
Authors: Xin An, Ru Yan, Shengjie Guo, Ting Xue, Huali Ma, Meiting Chen, Fangjian Zhou, Kai Yao, Pei Dong, Zhiling Zhang, Zhuowei Liu, Yanxia Shi, Hui Han
Journal: Journal of Clinical Oncology (2022)

5037 Background: Advanced penile squamous cell carcinoma (PSCC) is a rare disease with a poor prognosis. We performed a monocentric, Simon’s two-stage phase II study to evaluate the efficacy and safety of PD-1 blockade plus anti-EGFR target therapy and chemotherapy as neoadjuvant therapy in patients with locally advanced PSCC. We previously reported promising results in the first stage. The enrollment of the second stage had been completed by January 2022, herein we reported the updated results. Methods: Patients with chemotherapy-naive, locally-advanced PSCC (cT4 or cTxN3M0) were enrolled. The neoadjuvant regimen consists of anti–PD-1 antibody toripalimab, anti–EGFR antibody nimotuzumab, and chemotherapy (albumin-bound paclitaxel plus cisplatin and ifosfamide). Curative surgery was performed following a maximum of four cycles of treatment. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include overall response rate (ORR), relapse-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: A total of 29 patients were enrolled in two stages, with a median age of 57 (range 31-71) years. Till January 2022, 21 patients had completed the neoadjuvant treatment, 17 (81%) achieved an objective response, (CR 5, PR 12), 2 had SD, and 2 showed PD. Among 18 patients who underwent radical surgery, 11 showed no residual tumor on histopathology, with a pCR rate of 61.1% (11/18). The median follow-up time was 10.6 months. Two patients with PD died from disease, and 2 patients who experienced disease relapsed after radical surgery, in which 1 with SD, and 1 with PR. No relapse was observed among patients with pCR. The survival data are still immature. No unexpected toxicities and treatment-related death were recorded. Five out of 21 (23.8%) patients experienced grade 3 or 4 TRAEs. Grade 3 neutropenia occurred in 3 (14.3%) patients with 10 used G-CSF prophylaxis. No febrile neutropenia occurred. Other grades 3 toxicities included 1 case of peripheral sensory neuropathy and 1 anemia. The most common grade 1/2 TRAEs were alopecia (100%), decreased appetite (85.7%), nausea (71.4%), peripheral sensory neuropathy (66.7%), anemia (66.7%), neutropenia (33.3%), and infusion-related reactions (28.6%). The most common immune-related adverse events (IRAEs) were grade 1/2 hypothyroidism (19.0%), and grade 1 hyperthyroidism (4.8%). No severe IRAEs including pneumonitis, colitis, and myocarditis were observed. Conclusions: The triple combination is a provoking safe and efficacious neoadjuvant regimen for patients with advanced PSCC. Clinical trial information: NCT04475016.
VISIOCYT1 clinical trial: Artificial intelligence for the diagnosis of bladder urothelial lesions.
Authors: Thierry Lebret, Camélia Radulescu, Laurent Guy, Mathieu Roumiguié, Monique Courtade-Saïdi, Eric Piaton, Gregory Verhoest, Nathalie Rioux, Laurent Savareux, Stéphane De Vergie, Karine Renaudin, Christine Kandel, Samia Gonzalez, Ruth Borgès, Béatrix Cochand-Priollet, Sebastien Nivet, Geraldine Pignot
Journal: Journal of Clinical Oncology (2022)

e16558 Background: Voided urinary cytology is a non-invasive test, but it suffers from a lack of sensitivity (Se), particularly in low-grade urothelial lesions, and it remains pathologist-dependent. In order to improve the performance of urinary cytopathology, the VitaDX company (France) developed a medical device which uses whole-slide digitalization and artificial intelligence algorithms to identify tumor cells. The device allows complete analysis of morphological characters of voided urothelial cells, such as the shape, size and color of the nuclei. Methods: VISIOCYT1 is a prospective, multicenter clinical trial involving 319 patients divided into two groups: 1) patients with non-muscle invasive bladder tumors (NMIBC) confirmed by histology, and 2) control patients with negative urinary cytology and cystoscopy. The primary objective of the study was to evaluate the Se of the VisioCyt test. Specificity (Sp) and comparison of Se and Sp of conventional urinary cytology vs. the VisioCyt test were also calculated. Results: A total of 319 patients were included (170 in the NIMBC group vs. 149 controls). Overall Se was 80.9% and 45.9% for VisioCyt test and conventional urinary cytology, respectively (p = .002). Negative cytology being an inclusion criterion, a 100% Sp was attributed to the control group. It was calculated at 61.8% for the VisioCyt test. Concerning grade, the VisioCyt test allowed higher Se to be obtained in the low grade tumor category (66.7% vs. 26.1% for conventional urinary cytology, Mc Nemar test, p &lt; .0001). A higher Se was also observed in high grade tumors: 93.7% vs. 62.8% (p &lt; .0001). Conclusions: The VisioCyt test greatly improves the performance of urinary cytopathology in the diagnosis of urothelial bladder tumors, particularly in low grade, pTa lesions. Its implementation could dramatically reduce the need for cystoscopy in patients followed after conservative treatment of bladder cancer. Clinical trial information: NCT02966691. [Table: see text]
DIPG-41. Multi-omic profiling of patient-derived subclones identifies aggressive cellular subpopulations in paediatric diffuse high-grade gliomas (PDHGGs)
Authors: Ketty Kessler, Yura Grabovska, Anna Burford, Sara Temelso, Haider Tari, Valeria Molinari, Shauna Crampsie, Lu Yu, Jyoti Choudhary, Paula Proszek, Michael Hubank, Alan Mackay, Chris Jones
Journal: Neuro-Oncology (2022)

Abstract Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients &amp;gt;3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We have sought to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS-FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion-migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity-tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.
Universal health coverage and incarceration
Authors: Tyler N A Winkelman, Kayla C Dasrath, Jesse T Young, Stuart A Kinner
Journal: The Lancet Public Health (2022)

Global progress towards universal coverage of essential health services, a component of UN Sustainable Development Goal (SDG) 3.8, is measured at the country level using the WHO Service Coverage Index. However, data collection for this crucial metric excludes prisons and youth detention centres, despite the health needs in these settings, chronic underinvestment in custodial health care, and poor health outcomes for people released from custody in most countries. Particularly in countries with high incarceration rates, failure to include custodial settings in calculations of the service coverage index might result in overestimation of progress towards SDG 3.8.1, and mask important health inequalities. In this Viewpoint, we explore how failure to consider custodial settings in calculation of the service coverage index contributes to health inequalities and impedes progress towards SDG 3. We recommend explicitly considering all custodial settings in future estimates of progress towards universal health coverage.
Placebo response is up to four times more in conventional drugs compared to herbal medicine in male LUTS: A systematic review and meta-analysis
Authors: H. Mostafaei, A. Naseri, B. Pradere, K. Mori, T. Kawada, R. Sari Motlagh, T. Yanagisawa, F. Quhal, E. Laukhtina, P. Rajwa, A. Aydh, F. König, M. Pallauf, H. Salehi-Pourmehr, N. Kabiri, S. Hajebrahimi, S.F. Shariat
Journal: European Urology (2022)
QOL-11. Comparison of Neuropsychological Functioning in Pediatric Posterior Fossa Tumor Survivors: Medulloblastoma, Low-Grade Astrocytoma, and Healthy Controls
Authors: Cara Levitch, Alice Ann Holland, Jesse Bledsoe, Soo Young Kim, Marie Barnett, Sameera Ramjan, Stephen Sands
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Neuropsychological comparison of medulloblastoma (MB) and cerebellar low-grade astrocytoma (LGA) survivors to controls can clarify treatment-related neurocognitive late effects. While both brain tumor groups undergo surgery to the posterior fossa, children with MB additionally receive craniospinal irradiation with boost and chemotherapy. This study provides an updated comparison of neuropsychological functioning in these two groups and examines effects of demographic risk factors upon outcomes. PROCEDURE: Forty-two children (16 MB, 9 LGA, 17 controls) completed measures of intellectual functioning, verbal learning/memory, visual-motor integration, and fine motor functioning. The effects of age at diagnosis, time since diagnosis, gender, fatigue, and social status on neuropsychological functioning were examined. RESULTS: MB survivors demonstrated the worst neurocognitive late effects, but they were less severe and extensive than in prior studies. LGA survivors’ mean scores were below normative expectations in working memory, processing speed, and fine motor functioning. Additionally, parents of LGA survivors reported the most difficulty with behavior and cognitive regulation compared to healthy controls and medulloblastoma survivors. In this overall sample, processing speed difficulties were independent of fine motor functioning and fatigue. Higher parental education was associated with better intellectual functioning, working memory, delayed recall, and visual-motor integration. Neuropsychological function was not associated with gender, age at diagnosis, or time since diagnosis. CONCLUSION: The results support that contemporary treatment approaches with craniospinal irradiation plus boost and chemotherapy confer the greatest risk for late effects, while surgical resection is associated with subtle but important neurocognitive difficulties. Ultimately, this study furthers our understanding of factors impacting neuropsychological function in pediatric MB and LGA survivors and contributes to empirical support for close monitoring and targeted interventions into survivorship.
Reply to Ruobing Lei, Yuehuan Li, and Yaolong Chen’s Letter to the Editor re: Katharina Beyer, Lisa Moris, Michael Lardas, et al. Updating and Integrating Core Outcome Sets for Localised, Locally Advanced, Metastatic, and Nonmetastatic Castration-resistant Prostate Cancer: An Update from the PIONEER Consortium. Eur Urol 2022;81:503–14. Improving the Methodological Quality of Prostate Cancer Core Outcome Sets in Future Updates
Authors: Katharina Beyer, Steven MacLennan, Mieke Van Hemelrijck
Journal: European Urology (2022)
Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial
Authors: José Manuel Pérez-García, Marta Vaz Batista, Patricia Cortez, Manuel Ruiz-Borrego, Juan Miguel Cejalvo, Juan de la Haba-Rodriguez, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, María Gion, Monica Nave, María Fernández-Abad, Alejandro Martinez-Bueno, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Sofía Braga
Journal: Neuro-Oncology (2022)

Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement.This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3.As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis.T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.
IMG-05 Imaging characteristics of CNS NB-FOXR2 – a retrospective and MULTI-INSTITUTIONAL DESCRIPTION OF 25 CASES
Authors: Anna Tietze, Maarten H Lequin, Brigitte Bison, Liz Ivarsson, David Mirsky, Alok Jaju, Ulrike Löbel, Katja von Hoff, Kshitij Mankad
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The CNS neuroblastoma with forkhead box R2 (CNS NB-FOXR2) activation is one of the new embryonal tumor entities in the WHO CNS tumor classification 2021. The data currently available suggest a comparably favourable outcome after craniospinal irradiation and chemotherapy. The entity is poorly characterized on imaging. We therefore aimed to describe imaging features in a multi-center patient cohort. MATERIAL AND METHODS: Molecularly and histologically confirmed CNS NB-FOXR2 tumors were retrospectively collected at six pediatric oncology centers. The imaging features on preoperative MRI and CT data were recorded by 8 experienced pediatric (neuro)radiologists in consensus. RESULTS: Twenty-five patients were identified (13 females). The majority of tumors were large at presentation (mean 115 ± SD 83 ml), showed mostly none or little perifocal edema, enhanced only partly, were often calcified and/or hemorrhagic, were always T2w hyperintense to gray matter, and often had cystic and/or necrotic components. The min. mean ADC values were relatively low (mean 687.8 ± SD 136.3 in 10-6mm2/s). The tumors originated never infratentorial and were never centered in the midline. Metastases were rare. CONCLUSIONS: For the first time, imaging characteristics of the recently described CNS NB-FOXR2 are described in a multi-center cohort. The results of this study may assist in diagnosing these tumors preoperatively. Collaborative pooling of cases is important to gain insight into typical imaging features of rare tumors, especially in view of the increasing molecular-driven subtyping.
Immunotherapy treatment responses in hepatocellular carcinoma patients with nonalcoholic fatty liver disease cirrhosis.
Authors: Jeremy Chang, Joseph S Ryan, Veeral Ajmera, Kathryn J Fowler, Stephanie Ting, Pablo Tamayo, Adam Burgoyne
Journal: Journal of Clinical Oncology (2022)

e16199 Background: Primary liver cancer is the third most frequent cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) composing 75% of cases. Recent preclinical models suggest that immunotherapy targeting programmed cell death protein 1 (PD-1) leads to CD8+ T-cell activation but not tumor regression in nonalcoholic fatty liver disease (NAFLD) induced HCC. However, additional studies are required to understand the response of NAFLD-associated HCC patients to PD-1 and programmed death-ligand 1 (PD-L1) therapies. Methods: Our team conducted a retrospective, single center study to determine the best responses to anti-PD-1/PD-L1 containing regimens in patients with HCC and underlying NAFLD cirrhosis. There were 2 groups included in this study: patients with HCC associated with NAFLD cirrhosis and those who had HCC without NAFLD cirrhosis. All patients included in this study received either an anti-PD-1/PD-L1 targeted agent as monotherapy or combined with other systemic treatment. Radiologic evaluations were conducted between February 2018 and January 2022. Results: There were 81 patients were included in this study: 15 in the NAFLD cirrhosis HCC group and 66 in the HCC group without NAFLD cirrhosis. When determining the best responses to anti-PD-1/PD-L1 therapies, 6 patients (40%) with HCC and NAFLD cirrhosis had disease progression as their best responses versus 7 patients (10.6%) who had HCC without NAFLD cirrhosis (risk ratio 3.8, p = 0.012). Furthermore, in the HCC group without NAFLD cirrhosis, 59 patients (89.4%) experienced disease control (defined as stable disease, partial response, or complete response) from anti-PD-1/PD-L1 containing regimens compared to 9 patients (60%) in the NAFLD cirrhosis-related HCC group (risk ratio 1.5, p = 0.012). No significant differences were found in gender, patient age, or treatment regimens received between the two groups. See the table below for details on immunotherapy regimens and treatment responses. Conclusions: In this study, HCC patients with NAFLD cirrhosis experienced significantly higher rates of disease progression as the best response to anti-PD-1/PD-L1 therapies compared to HCC patients without NAFLD cirrhosis. As the use of immunotherapy in the HCC population continues to expand, additional prospective studies are necessary to clarify the impact of underlying liver disease on treatment response.[Table: see text]